SUMMARY Despite advances in the development of targeted chemotherapeutic agents, oral mucositis secondary to conventional chemotherapy and radiation remains one of the most frequently encountered toxicities associated with cancer therapy. It leads to both costly and debilitating symptoms and, in severe cases, a worsened prognosis for the patient. Oral mucositis occurs in up to 100% of cases of head and neck cancer and 60 ? 90% of cases of hematopoietic stem cell transplants. Acute DNA damage caused by conventional chemotherapy and radiation leads to rapid hyperactivation of a group of DNA-repairing enzymes known as poly-ADP-ribose polymerases (PARPs) that utilize nicotinamide adenine dinucleotide (NAD+) as a co-substrate. The depletion of NAD+ leads to a decrease in the activity of SIRT1, an NAD+-dependent deacylase that suppresses inflammation. In the past few years, NAD+ precursors have emerged as one of the most exciting molecules in medical research. We hypothesize that maintenance of NAD+ levels in oral mucosa by treatment with the NAD+ precursor nicotinamide mononucleotide (NMN) will greatly reduce the inflammatory cascade and greatly reduce the severity and duration of oral mucositis, providing a novel path to preventing and treating this debilitating condition. To test this hypothesis we will perform both in vitro and in vivo studies modeling the pathology of oral mucositis. In Aim 1, we will study the protective and anti-inflammatory effects of NMN in in vitro oral cells and trace the flux of NAD+ using isotopically labeled NMN. In Aim 2 we will utilize a hamster radiation-induced oral mucositis model to evaluate if topical NMN delays the onset, reduces the peak, dampens the total extent, and promotes resolution of mucositis. In Aim 3 we will explore the mechanisms by which NMN attenuates mucositis by testing if SIRT1 is a key regulator of oral mucositis that mediates the anti- inflammatory activities of NMN. These experiments will systematically evaluate whether an NAD+ precursor can effectively mitigate oral mucositis and guide the development of safe and effective treatments to cut the costs of cancer treatment in the US and significantly improve quality of life for cancer patients.